Often responses of cells studied with the tight-seal whole-cell recording technique differ from those of intact cells and change with time. We have developed an instrumental array capable of simultaneous physiologic and anatomic realtime measurements of living cells with control of the internal millieu, first using it to measure the capacitance of secretory cells. We have devised a method for purification of mast cells. Large capacitance changes are seen at the instant of secretion in mast cells, consistent with the calculated area of the secretory granule. We also applied the cell activating compound acetylcholine to a variety of rat lacrymal gland cells to measure the liberation of intracellular calcium. We conclude that there is a loss of a diffusible factor that acts after muscarinic receptor binding and before polyphosphoinositol release. Techniques are currently being developed to prevent the loss of such factors.